Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes

Bassano, Irene; Ong, Swee Hoe; Lawless, Nathan; Whitehead, Thomas; Fife, Mark; Kellam, Paul

doi:10.1186/s12864-017-3801-8

Cited by 11 publications

(11 citation statements)

References 58 publications

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“…One family of ISGs that functions as broad-spectrum inhibitors of viral replication is the interferon-inducible transmembrane protein (IFITM) family. IFITMs are functionally conserved across many species, including birds (9–12), pigs (13, 14), and bats (13). In most cases, this family of restriction factors blocks infection during virus entry into cells (15), although additional mechanisms have been proposed (16, 17).…”

Section: Introductionmentioning

confidence: 99%

Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane

Smith

Busse

Binter

et al. 2019

J Virol

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The acute antiviral response is mediated by a family of interferon-stimulated genes (ISGs), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with increased susceptibility to viral infections. One family of ISGs with antiviral function is the interferon-inducible transmembrane proteins (IFITMs), of which IFITM3 has been studied extensively. In contrast, IFITM1 has not been studied in detail. Since IFITM1 can localize to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of Paramyxoviridae and Pneumoviridae, including respiratory syncytial virus (RSV), mumps virus, and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localization for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localization of the protein and reduced antiviral activity. By screening reported data sets, 12 rare nonsynonymous single nucleotide polymorphisms (SNPs) were identified in human IFITM1, some of which are in the CIL domain. Using an Ifitm1−/− mouse, we show that RSV infection was more severe, thereby extending the range of viruses restricted in vivo by IFITM proteins and suggesting overall that IFITM1 is broadly antiviral and that this antiviral function is associated with cell surface localization. IMPORTANCE Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon-stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane is interferon-inducible transmembrane protein 1 (IFITM1). Here we demonstrate that IFITM1 can inhibit infection with a range of viruses that enter via the plasma membrane. Mutant IFITM1 proteins that were unable to localize to the plasma membrane did not restrict viral infection. We also observed for the first time that IFITM1 plays a role in vivo, and Ifitm1−/− mice were more susceptible to viral lung infection. These data contribute to our understanding of how ISGs prevent viral infections.

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Section: Introductionmentioning

confidence: 99%

Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane

Smith

Busse

Binter

et al. 2019

J Virol

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“…Interestingly, the prediction revealed three differences in the IFITM3 protein between mammals and birds. However, this prediction was carried out on limited species of mammals and birds registered in GenBank, further confirmation in recently reported IFITM3 sequences is needed in the future (Bassano et al 2017). In a previous topology study in the human IFITM3 protein, substantial evidence indicated that the human IFITM3 protein favors the cytosolic Nterminus.…”

Section: Discussionmentioning

confidence: 66%

Genetic characteristics and polymorphisms in the chicken interferon-induced transmembrane protein (IFITM3) gene

Kim

Jeong

2019

Vet Res Commun

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The interferon-induced transmembrane protein 3 (IFITM3) gene is classified as a small interferon-stimulated gene and is associated with a broad spectrum of antiviral functions against several fatal enveloped viruses, including influenza A viruses (IAVs). The rs12252 single nucleotide polymorphism (SNP) of the IFITM3 gene in humans was associated with susceptibility to H1N1 influenza in a 2009 pandemic. In addition, overexpression of the IFITM3 protein potently inhibits the highly pathogenic avian influenza H5N1 virus in ducks and chickens. Although chickens are a major host of influenza viruses and the IFITM3 gene participates in the host antiviral system, studies on chicken IFITM3 gene are very rare. To investigate the genetic characteristics of the chicken IFITM3 gene, we performed direct sequencing and alignment in 108 Dekalb White and 72 Ross breeds. We also investigated the genotype and haplotype frequencies and linkage disequilibrium of the IFITM3 gene polymorphisms and evaluated whether the non-synonymous SNPs are deleterious. We found significantly different genotype, allele and haplotypes frequencies between two chicken breeds, Dekalb White and Ross. Furthermore, we compared and analyzed the promoter structure of the chicken IFITM3 gene with that of several species. We found that birds have a long C-terminal domain and inverted topology of the IFITM3 protein compared to mammals. We also identified fourteen genetic polymorphisms in the chicken IFITM3 gene. L100 M and N125H were predicted as 'probably damaging' and L100 M can alter the length of its conserved intracellular loop (CIL). Furthermore, chickens, but not mammals, contain CpG islands (CGIs) in this promoter region.

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“…The chicken IFITM ( chIFITM ) genes are clustered on chromosome 5, and to date, four genes have been annotated, namely chIFITM1 , chIFITM3 , chIFITM5 and chIFITM10 [ 50 ]. Although not yet annotated in the Gallus gallus reference sequence, studies show the existence of chIFITM2 and suggest a hypothetical genetic structure of the locus based on the human syntenic genome region [ 51 ]. The mammalian IFITM proteins are relatively small (about 130 amino acids) [ 33 ] and share a topology defined by a conserved CD225 domain, consisting of two intramembrane (IM) regions and a conserved intracellular loop (CIL) [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

The Characterization of chIFITMs in Avian Coronavirus Infection In Vivo, Ex Vivo and In Vitro

Steyn

Keep

Bickerton

et al. 2020

Genes

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The coronaviruses are a large family of enveloped RNA viruses that commonly cause gastrointestinal or respiratory illnesses in the infected host. Avian coronavirus infectious bronchitis virus (IBV) is a highly contagious respiratory pathogen of chickens that can affect the kidneys and reproductive systems resulting in bird mortality and decreased reproductivity. The interferon-inducible transmembrane (IFITM) proteins are activated in response to viral infections and represent a class of cellular restriction factors that restrict the replication of many viral pathogens. Here, we characterize the relative mRNA expression of the chicken IFITM genes in response to IBV infection, in vivo, ex vivo and in vitro using the pathogenic M41-CK strain, the nephropathogenic QX strain and the nonpathogenic Beaudette strain. In vivo we demonstrate a significant upregulation of chIFITM1, 2, 3 and 5 in M41-CK- and QX-infected trachea two days post-infection. In vitro infection with Beaudette, M41-CK and QX results in a significant upregulation of chIFITM1, 2 and 3 at 24 h post-infection. We confirmed a differential innate response following infection with distinct IBV strains and believe that our data provide new insights into the possible role of chIFITMs in early IBV infection.

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Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes

Cited by 11 publications

References 58 publications

Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane

Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane

Genetic characteristics and polymorphisms in the chicken interferon-induced transmembrane protein (IFITM3) gene

The Characterization of chIFITMs in Avian Coronavirus Infection In Vivo, Ex Vivo and In Vitro

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